2-(2&#39;-thenyl)-4, 5-dihydroimidazoles and process for making the same



Patented Dec. 21, 1948 uuirso m (2'-THENYL $1 445.nirrYnRmMmAzoLEs ANDPROCESS FOR MAKING THE SAME Lucas I. Kyrides, St. Louis, Mo., assignorto Monsanto Chemical Company, St. Louis, Mo., a cornotation of Delaware0 No Drawing. fApplication February 13, 1946, Serial No. 647,430

This invention relates to therapeutic agents and more particularly tonovel therapeutic agents containing the thiophene radical,

According to the present invention g en'er'ally stated, an ester of 2thieny1 acetic acid and'anhydrous ethylenediamine is heated withanhydrous ethylenediamine under reflux conditions with concomitantremoval of the corresponding alcohol formed in the reaction from thereaction mixture by fractionation. I The reaction mixture is thereafterfractionally distilled at reducedpressure to recover first a fraction ofunreacted ethyl enediamine and subsequently a fraction of 2-(2'-'thenyl) l,5dihydroimidazole. The process is desirably repeated on thehigh boiling residuewith the addition of alkyl Z th'ienylacetate andanhydrous ethylenediamine thereto. The combined yields'of 2-(2'-thenyl)-4,5dihydroimidazole are very good. I v

In place of an ester of 2-thienyl acetic'acid in theaforedescribedprocess, an ester of 5-inethyl- Z-thienyl acetic acid may be employedand the resulting product is 2(5"-"nethy1-2-thenyl)4,5-dihydroimidazole. The starting material, 5 methyl-Z-thienyl acetic acid,may be prepared by chloromethylating Z-methylthiophene to produce5-methyl-2-chloromethylthiophene. The chloro compound is then furtherprocessed, for example as described in J, A. C. S. as, 2945 (1941), byreacting the chloro derivative with sodium cyanide to obtain5-methyl-2--thienyl acetonitrile. The nitrile is then hydrolyzed, forexample with caustic soda in aqueous alcohol solution. After thehydrolysis is complete, the reaction mixture is acidified to liberate5-methyl-2-thienyl acetic acid. This material is then separated, washedand dried. 5-methyl-2-thienyl acetic acid is subsequently esterified,for example with ethyl alcohol in the presence of 1% sulfuric acid.

The novel compounds of the present inven tion have the formula:

the

The following examples will serve to illustrate e Glaiins. (o1.etc-309.6)

the process for thepreparation of the novel compounds of the presentinvention:

Example I A mixture of 57 g. (0.363 mole) of methyl 2--thlenyl acetateand 110 g. (1.83 moles) of anhydrous -ethylenediamine was refluxed for"12 hours while methyl alcohol was removed as formed through a 6-platecolumn; The excess ethylenediamine was removedby distillation and he2-(2-thenyl)--l,5-dihydroimidazole formed the reaction was thendistilled off; B. P. 165 171') C. at 9 mm- Yield, 34g. To the highboiling residue remaining in the flask there Was added 56 g. of methyl2--thienyl acetate and 140 g. of anhydrous ethylenediamine. The mixturewas refiuxed for 12 hours with the removal of methyl alcohol as formed.Then the excess ethylenediamine was removed and 120 cc. thereof wasadded back to the reactionmixture and the mixture was refluxed again for4 hours. The ethylenediamine was then removed by distillation and the2-(2': thenyl) -4,5dihydroimidazole was distilled off; 3. P. l6"-l70 C.at 9 mm. Yield, 52.8 g. Total yield 86.8 g. (72%).

Example H f Amixtureof 62 g, (0.363'mole) of methyl-(5,-methy1-2-thienyl) acetate and 110 g. (1.83 moles) of anhydrousethylenediamine was refluxed for approximately 12 hours during whichtime methyl alcohol was fractionally distilled from the reaction mixturethrough a 6-plate column. Subsequently the excess ethylene diamine wasremoved from the reaction mixture by distillation and the2-(5-methyl-2-thenyl) 4,5 dihydroimidazole formed in the reaction wasthen distilled off. The residue in the flask was then processedaccording to the procedure decribed in Example I.

In preparing the novel compounds of the present invention, any ester ofZ-thienyl acetic acid or of 5-methyl Z-thienyl acetic acid may beemployed, for example the alkyl esters such as the ethyl, propyl,isopropyl, butyl, octyl and dodecyl esters, the aralkyl esters such asthe benzyl ester, the cycloalkyl esters such as the cyclopropyl,cyclobutyl or cyclohexyl esters and the aryl esters such as the phenylester.

The acid salts of the novel compounds of the present invention are alsouseful as pharmaceutic agents, for example salts such as thehydrochloride, sulfate, acid sulfate, salicylate, benzoate, phosphateand acetate. These salts may be prepared in aqueous or organic solventsolution by dissolving the novel compounds of the present inin Which Rrepresents a radical selected from the group consisting of hydrogen andmethyl, and acid salts thereof.

. v 2. 2=- (2"-thenyl) -4,5-dihydroimidazole. having the formula: I

3. 2-(5'-methyl-2'-thenyl) -4,5 dihydroimidazole, having the formula:H1ONH HO -FH Hr that L0H.

N s 4. A process for preparing a compound of the formula type:

H2C1TIH HO CH rm; o-oHi- -R in. which R represents a radical selectedfrom the group consisting of hydrogen and methyl, comprising heating acompound of the formula type:

H%-("3E 12-0 CCH2000RI in which R represents a radical selected from thegroup consisting of hydrogen and methyl and R1 represents a radicalselected from the group consisting of alkyl, aralkyl, and aryl radicals,with anhydrous ethylenediamine under reflux conditions with concomitantremoval of the alcohol formed in the reaction, and recovering from thereaction mixture a product having a formula of the type hereinabovedescribed.

5. A process for preparing 2-(2-theny1)-4=,5- dihydroimidazolecomprising heating an ester of 2-thienyl acetic acid with anhydrousethylenediamine under reflux conditions with concomitant removal of thealcohol formed in the reaction', and recovering2-(2'-thenyl)-4,5-dihydroimidazole from the reaction mixture.

6. A process for preparing 2-(5'-methy1-2"- thenyl)-4,5-dihydroimidazole comprising heating an ester of 5-methyl-2-thienylacetic acid with anhydrous ethylenediamine under reflux conditions withconcomitant removal of the alcohol formed in the reaction, andrecovering 2-(5- methyl-2-thenyl) -4,5-dihydroimidazole from thereaction mixture. v

"7. A process for preparing 2-(2'-thenyl)-4,5- dihydroimidazolecomprising heating an. ester of 2-thienyl acetic acid with anhydrousethylenediamine under reflux conditions with concomitant removal of thealcohol formed in the reaction, fractionally distilling off unreactedethylenediamine and subsequently distilling off 2- (2' -thienyl)-4,5-dihydroimidazo1e. g

8. A process for preparing 2-(2'-thenyl)-4,5 dihydroimidazole comprisingheating the methyl ester of 2-thienyl acetic acid with anhydrousethylenediamine under reflux conditions with concomitant removal ofmethyl alcohol, and recovering 2- (2'-then.yl) -4,5-dihydroimidazolefrom the reaction mixture.

19. A process for preparing 2-(5'-methyl-2'- thenyl)-4,5-dihydroimidazo1e comprising heating the methyl ester of 5-methyl-2-thienylacetic acid with anhydrous ethylenediamine under reflux conditions withconcomitant removal of methyl alcohol formed in the reaction, andrecovering 2-(5'-methyl-2'-thenyl) -4,5-dihydroimidazole from thereaction mixture.

LUCAS P. KYRIDES.

No references cited.

